NM_006758.2:c.132+18del

U2AF1 · NP_006749.1:p.? · NM_006758.2

GRCh37: chr21:44524406 GA>G · GRCh38: chr21:43104296 GA>G

Gene: U2AF1 Transcript: NM_006758.2

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

U2AF1

Transcript

NM_006758.2

Protein

NP_006749.1:p.?

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_006758.2:c.132+18del is an intronic deletion (intron 2, +18) in U2AF1. It is absent from gnomAD v4.1 (0/6520 alleles), meeting PM2 at moderate strength.

SpliceAI predicts no splice impact for this variant (max delta = 0.00), meeting BP4 at supporting benign strength.

PVS1 is not applicable: this intronic variant does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice site) under ClinGen SVI PVS1 recommendations (PMC6185798). SpliceAI corroborates absence of splice effect.

The variant is absent from ClinVar, COSMIC, and the published literature. No functional studies, de novo reports, or segregation data are available.

With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is conflicting and insufficient to classify as likely pathogenic or likely benign. The variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 rules.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_006758.2:c.132+18del is an intronic deletion at position +18 of intron 2. It is not a null variant (nonsense, frameshift, initiation codon, or canonical ±1,2 splice site) and therefore does not meet PVS1 criteria under generic ACMG/AMP or ClinGen SVI PVS1 recommendations (PMC6185798). SpliceAI predicts no splice impact (max delta = 0.00).	pvs1_variant_assessment pvs1_gene_context spliceai
PS1	N/A	PS1 requires the same amino acid change as a previously established pathogenic variant. NM_006758.2:c.132+18del is an intronic deletion that does not alter the amino acid sequence; no protein consequence is defined.
PS2	Not met	No de novo occurrence data are available for NM_006758.2:c.132+18del. No publications or database records report this variant as de novo with confirmed paternity and maternity.
PS3	Not met	No well-established in vitro or in vivo functional studies have been performed for NM_006758.2:c.132+18del. No functional data were identified in the literature or curated databases.
PS4	Not met	No case-control or cohort data are available to assess whether the prevalence of NM_006758.2:c.132+18del is significantly increased in affected individuals versus controls.
PS5	N/A	PS5 is not a standard criterion in the ACMG/AMP 2015 classification framework (Richards et al., PMID:25741868). This variant is assessed under generic ACMG/AMP 2015 rules.
PM1	Not met	NM_006758.2:c.132+18del is located in intron 2 (+18), which is not within a characterized mutational hotspot or critical functional domain of U2AF1. Known U2AF1 hotspots are at residues S34 and Q157 within the coding region.
PM2	Met	NM_006758.2:c.132+18del is absent from gnomAD v4.1 (0/6520 alleles, AF = 0.0%), gnomAD v2.1, and gnomAD-Canada. This is consistent with PM2: absent from population databases at a frequency below 0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Skipped per adjudication instructions.
PM4	N/A	PM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. NM_006758.2:c.132+18del is an intronic deletion that does not alter protein length or coding sequence.
PM5	N/A	PM5 requires a novel missense variant at the same amino acid residue as a known pathogenic missense variant. NM_006758.2:c.132+18del is an intronic deletion, not a missense variant. Protein consequence is undefined (p.?).	pm5_candidates
PM6	Not met	No assumed de novo occurrence (without confirmation of paternity/maternity) has been reported for NM_006758.2:c.132+18del in any database or publication.
PP1	Not met	No cosegregation data are available for NM_006758.2:c.132+18del. Family studies have not been reported.
PP2	N/A	PP2 applies to missense variants in a gene with a low rate of benign missense variation and where missense is a common disease mechanism. NM_006758.2:c.132+18del is an intronic deletion, not a missense variant.
PP3	Not met	No computational evidence supports a deleterious effect. SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel are not applicable to non-SNV variants. No in silico tools predict pathogenicity for this intronic deletion.	spliceai
PP4	Not met	No patient phenotype or family history data are available to assess whether the proband's clinical presentation is specific for a U2AF1-related disorder.
PP5	Not met	NM_006758.2:c.132+18del is absent from ClinVar. No reputable source has reported this variant as pathogenic.	clinvar
BA1	Not met	NM_006758.2:c.132+18del is absent from gnomAD v4.1 (0/6520 alleles, AF = 0.0%). The allele frequency does not exceed the BA1 threshold of >1% in any population. The highest subpopulation frequency is 0.0% in all groups.	gnomad_v2 gnomad_v4
BS1	Not met	NM_006758.2:c.132+18del is absent from gnomAD (0/6520 alleles, AF = 0.0%). The allele frequency does not exceed the BS1 threshold of >0.3% (non-VCEP cutoff).	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding observation of NM_006758.2:c.132+18del in healthy adults with full penetrance expected at an early age.
BS3	Not met	No well-established in vitro or in vivo functional studies have been performed demonstrating no damaging effect for NM_006758.2:c.132+18del. While SpliceAI predicts no splice impact, this alone is insufficient to meet BS3 which requires experimental functional evidence.	spliceai
BS4	Not met	No cosegregation data are available to assess lack of segregation with disease for NM_006758.2:c.132+18del.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. NM_006758.2:c.132+18del is an intronic deletion, not a missense variant.
BP2	Not met	No data are available regarding observation of NM_006758.2:c.132+18del in trans with a pathogenic variant in a fully penetrant recessive disorder, or in cis with a pathogenic variant in a dominant disorder.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without a known function. NM_006758.2:c.132+18del is an intronic deletion, not an in-frame coding indel.
BP4	Met	SpliceAI predicts no splice impact for NM_006758.2:c.132+18del (max delta score = 0.00). For an intronic variant, the relevant computational evidence is splice prediction, and the sole applicable in silico tool indicates no effect. Other in silico tools (REVEL, BayesDel) are not applicable to non-SNV variants.	spliceai
BP5	Not met	No alternative molecular basis for disease has been identified in the proband that would explain the phenotype independent of NM_006758.2:c.132+18del.
BP6	Not met	NM_006758.2:c.132+18del is absent from ClinVar. No reputable source has reported this variant as benign.	clinvar
BP7	N/A	BP7 applies to silent (synonymous) variants for which splicing prediction algorithms predict no impact. NM_006758.2:c.132+18del is an intronic deletion, not a synonymous coding variant.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.